Welcome to Yale Cancer Center Answers with Dr. Francine Foss
and Dr. Lynn Wilson. I am Bruce Barber. Dr. Foss is a
Professor of Medical Oncology and Dermatology specializing in the
treatment of lymphomas. Dr. Wilson is a Professor of
Therapeutic Radiology and an expert in the use of radiation to
treat lung cancers and cutaneous lymphomas. If you would like
to join the conversation, you can contact the doctors
directly. The address is canceranswers@yale.edu and
the phone number is 1888-234-4YCC. This evening Francine and
Lynn are pleased to welcome Dr. Harriet Kluger and Dr. Mark
Faries. Dr. Kluger is an Associate Professor of Medical
Oncology and a member of the Yale Cancer Center Melanoma Program,
and Dr. Faries is an Associate Professor of Surgical Oncology
specializing in the treatment of melanoma. Here is Francine
Foss.

Foss
Let us start off with a little education about melanoma.
Could you tell us what it is?

Faries
Melanoma is a cancer that starts in the skin, in the pigment cells
of the skin, and it is associated with excessive sun or ultraviolet
radiation exposure. It is typically treated by surgery in an early
stage and with medical therapy if it is a more advanced
stage. It is a concerning cancer because it is one of the
fastest growing cancers in terms of incidence of any of the
cancers.

Foss
Mark, you are new to Yale, could you tell us a little bit about
when you came to Yale, where you came from, and what your interests
are?

Faries
I just arrived at Yale, and I am coming from Santa Monica,
California, so I did not come for the weather, but there are some
really great things about the Melanoma Program at Yale. One
is that it has a tremendous tradition in the treatment of melanoma
patients. The Yale Melanoma unit goes back thirty five years
and has been led by Steve Ariyan over the years, but there are a
lot of exciting things that are happening in the program now with
Harriet in the medical oncology group, and the new Smilow Cancer
Hospital, so it is a great time to be here.

Wilson
Harriet, tell us a little bit about your background. We have
known each other a long time and you have been at Yale a pretty
long time, but tell us your background and how you got interested
in melanoma.

Kluger
I came from a sunny place, I was born in South Africa where we had
a lot of sun exposure with the high altitude in Johannesburg, so I
became interested in it primarily from a personal perspective
because myself and a number of relatives had this problem.
When I moved to Yale in 1999 as an oncologist I decided to join the
Yale Melanoma Unit for similar reasons to those that Mark
gave. There was a lot going on at the time, there were a lot
of opportunities for delivering novel therapies to melanoma
patients as opposed to some diseases such as breast cancer where
they had made much more progress. We viewed this as an
opportunity to make progress and to really contribute to a disease
for which there was very little to offer.

Foss
Harriet, could you outline for us the Melanoma Program at
Yale. I understand it is a multidisciplinary program.
Could you, for our listeners, go through the different types of
folks who are participating in the program?

Kluger
We have physicians and scientists and then we have hybrids who do
both science and clinical work. On the clinical side, we have
dedicated radiologists who come to weekly meetings where we discuss
patients. We have dedicated skin pathologists as well as
surgical pathologists. We now have an epidemiologist who
comes to our meetings and is involved in genetic screening of
patients, we also have surgeons both on the plastic surgery side
and the surgical oncology side. We have radiation therapists
who focus on brain metastases for melanoma, a separate radiation
therapist who does radiation on the other parts of the body and
then we have the medical oncologists who deliver what we call
systemic therapies, so therapies that are either injected or
ingested. On the science side, we have Dr. Ruth Halaban who
is the lead basic scientist, and we have computational scientists
as well, so people who analyze data from the high throughput
experiments that we do, we have statisticians as part of the group
and we have a number of other scientists who do a lot of melanoma
related research and drug development primarily.

Wilson
Mark, how is the diagnosis usually made? You mentioned that there
can be some different treatments depending on early versus later
disease. Tell us about that, and since you are a surgeon I
take it you are probably involved in making this diagnosis fairly
often.

Faries
Most often the diagnosis is made by a dermatologist or by the
patient's primary care physician, and typically it will be a skin
lesion that either the patient or the physician has noted is
unusual, that has some suspicious features to it. The
features that we look for are the A, B, C, D characteristics, where
A is for asymmetry, something that is not nice and round or
oval. B is for irregular or ragged border. C is for the
color, which can have multiple colors in it, brown and red or blue
and black or a color that is different from the color of the
patient's other moles, and D is diameter which is a bit of a weak
indicator but the larger it is, the higher the risk. Really
the thing to look for is a skin lesion that is different, that is
unusual, that does not match up with other things that a particular
patient has on the skin and that would raise someone's suspicion
that it might be a problem and should lead hopefully to an early
biopsy.

Foss
How are most melanomas diagnosed? Are they diagnosed because
a patient notices something or a primary care physician notices
something? What is the most common way that these are picked
up?

Faries
It can be in both ways, and it depends a lot on the awareness of
both the physician and the patient and many times skin lesions can
be ignored both by the patient and by a physician and melanoma is
allowed to progress to a more advanced stage. It is important
that does not happen. It is important that these are picked
up early. The earlier the melanoma is picked up, the simpler
the treatment the more likely that the patient will be cured and so
at an early stage we would simply excise that area with or without
lymph node evaluation and most of those patients will be fine.

Wilson
Are these usually brand new, or is it a mole that might have been
present for thirty years and started to change, or are both
scenarios possible?

Faries
Both are possible and it's fairly equally distributed between the
two, so if you have a mole that has been there forever, but has
recently changed, that's something you should be concerned about
and if there is a new mole or a new dark spot that appeared where
there had not been anything before, that is the other typical way
that it appears.

Wilson
Do these have symptoms? Do they hurt, are they itchy, or do
they bleed?

Faries
Often symptoms come though at a later stage and so optimally no
melanoma would be picked up before there are any symptoms.
Itching can sometimes be a symptom and then bleeding if a melanoma
has got to a point where it is ulcerated.

Foss
Harriet, you mentioned epidemiology. I wonder if you could
comment on whether there are any other associated risk factors for
melanoma such as family history or other genetic risk factors that
we should be aware of.

Kluger
Genetic risk factors have been identified, for example, there is a
gene called the P16 gene, which is mutated in actually a very small
percentage of patients with melanoma. There probably are lots
of additional genes that we have not identified yet. We do
know for sure that the strongest risk factor for developing
melanoma is sun exposure. The second one would be family
history, genetics, and so on. The other risk factor of course
is lifestyle, location, where you live, how close to the equator
and so on.

Foss
Can we just interject here, the average age for patients with a
melanoma, how young and how old?

Faries
The peak incidence is in the 50s and 60s, but melanoma is one of
the cancers that spreads across almost the entire age
spectrum. Because it can affect so many people at a young age
it robs us of more productive years of life than just about any
other cancer other than leukemias and lymphomas. So it is
unusual in very young children, but beyond that everyone needs to
be aware of melanoma as a possibility.

Foss
I was just going to ask about the increasing incidence in teenagers
and young adults, perhaps related to tanning bed use.

Faries
We are concerned about any unnecessary excessive ultraviolet
radiation exposure and one of the groups that we have seen a great
increase in melanoma has been relatively young woman who tend also
to be the ones who are most likely to use tanning beds. With
improved quality of some of the sunless tanning products that are
available now, hopefully there will be less of an interest for some
of these people.

Wilson
So a patient sees their primary care physician and a biopsy is
done and the diagnosis of melanoma is made, and the biopsy was done
in the primary care physician's office. What is the course of
events that that patient would traverse at that point?

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Faries
That is the point in which they are frequently referred to the
Melanoma Unit, typically to see one of the surgeons there, such as
myself. One of the most important things that can happen is
to have that biopsy looked at carefully because we get a huge
amount of information about how serious the melanoma is from the
characteristics of that original biopsy, so it is important that
they biopsy is done well and that it is examined well by an
experienced pathologist. From that point I would consult with
the patient and go over what the options are. What types of
treatments are available, and the best course for them to really
complete the picture of where they stand and then to get that
original primary melanoma treated.

Wilson
Why don't you both take us through some of the treatment options
for a patient.

Faries
For melanomas that are clinically localized to their primary site,
there is no sign of any melanoma anywhere else, what we do is
remove the area where that biopsy was performed, where the original
lesion was, with a rim of normal-appearing tissue around the
outside of it to be sure that every last cell that is in the area
that we can get out, we get out. It ends up being a fairly
sizeable excision that we do to be as thorough as possible, and
that is why reconstruction with plastic surgical techniquea is
important to be sure that the patient heals up as quickly and as
normally as they can. In some instances, when there are
characteristics of the melanoma that suggest it may have spread,
the most likely place for it to spread is to the lymph nodes in the
area of that primary melanoma. What we do in the modern era
is something called a sentinel lymph node biopsy and that is the
way that we can tell which one or two lymph nodes generally are the
ones that receive direct drainage of fluid from the tissues around
the primary tumor site. Those are the lymph nodes that will
hold any melanoma if it is spread, so we can evaluate those in a
minimally invasive way and complete the picture of where the
patient stands in terms of their treatment, and if there is more
advanced disease or more significant involvement of the lymph
nodes, then it may require additional surgery to remove more lymph
nodes and then the patient also begins to consider the possibility
of medical or systemic treatment to decrease the chance of a
melanoma showing up anywhere else.

Kluger
For systemic therapy, if the melanoma has only spread to the lymph
nodes and it has been completely resected, the standard therapy at
that point is a drug called interferon. We have a number of
other experimental therapies that we are currently trying in
clinical trials to see if we can improve the outcome and get better
benefit than what we get from the interferon, which is a tough drug
to take. Primarily, the focus is on immune therapies, so we
are trying to boost the immune system to take care of any rogue
melanoma cells that might have escaped beyond the lymph node that
was just resected. If the melanoma has spread beyond the
lymph nodes and is no longer resectable, then the patient has what
we call stage IV disease and there too we have a number of standard
therapies and a number of experimental therapies which we can
discuss a little bit later on.

Wilson
Thanks guys, we are going to take a short break for a medical
minute. Please stay tuned to learn more information about
melanoma with Dr. Kluger and Dr. Faries.

Wilson
Welcome back to Yale Cancer Center Answers. This is Dr. Lynn
Wilson, and I am joined by my co-host Dr. Francine Foss.
Today we are joined by Dr. Harriet Kluger and Dr. Mark Faries and
we are discussing melanoma. Harriet, before the break we were
talking about more advanced disease and you were about to give us
some more details about various treatment options. Why don't
you discuss that with us and then talk to us a little bit about
some of the clinical trials that are available for patients.

Kluger
Once the melanoma has spread beyond the lymph nodes and is no
longer resectable surgically, we have to try to treat the melanoma
with either drugs that are ingested by mouth or something that is
injected intravenously or subcutaneously. The standard of
care in our minds is a drug called high-dose interleukin-2, and
this drug has been available for well over a decade. The nice
thing about this drug is that it is given in-house for a very brief
period. They come in for one week, they go home for week and
come back for another week, and then if it is working, we do that
again. It is tough to take while the patient is in-house but
once they are discharged a few days later they recover and they can
go back to their normal lives. The patients that respond to
that drug tend to have a really durable response, in fact, there
were patients that were treated in the 1980s who have never had a
recurrence. For that reason, we tend to try to start with it
for the robust patient who can tolerate it.
There are a few chemotherapy drugs that have been given over the
years. They do work in a percentage of patients, but the
duration of the response of those drugs tends to be a little bit
more limited. We now have two new very promising drugs that
probably will be approved by the FDA soon. One is an immune
therapy that we hope will be approved sometime in 2011, it is a
drug called Ipilimumab. I can test you afterwards to see if
you remember the name, but we just call it Ipi for short. It
is also an immune-based therapy, and essentially
what it does is it takes the

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breaks of the immune system so we get some nonspecific immune
activation and patients tend to respond for prolonged periods of
time and patients also tend to live longer when they receive
Ipilimumab. The other drug that is looking very promising, is
a targeted therapy developed by a company called Plexxikon.
There were a number of articles about this drug in the New York
Times recently and the patients who have a certain mutation in
their melanomas, it is approximately 50% of the melanoma patients,
have dramatic responses to this drug as well and the duration of
response is probably in the order of nine months.

Foss
Harriet, can you tell us how surgery is being integrated with
medical oncology in terms of clinical trials and developing new
strategies for treating these melanomas?

Kluger
Sometimes we have a patient who has a single site of metastasis or
a couple of sites of metastasis and we can then give medical
therapy before we go for surgery and that gives an opportunity to
learn a lot about the disease. We call that neoadjuvant
treatment and sometimes we do that for patients whose disease has
spread beyond the draining lymph node, sometimes we only do it for
regional disease as well and perhaps Mark can elaborate on that a
little bit because he has been involved in some of those trials at
John Wayne Cancer Center in the past.

Faries
From a surgical perspective the developments that Harriet has
described, these new medical treatments, are really exciting and
something that has not happened in melanoma before to have these
new treatments that are effective when so few things have been
shown to be effective in the past, and what that allows us to do is
that in some patients who have a response to some of these new
treatments but not a complete response, there is perhaps one or two
lesions that are left in place that have not gone completely away,
is go ahead and remove those lesions surgically and what we have
seen with some of the systemic treatments where patients have
partially responded, is that if we go ahead and remove those other
spots those patients tend to do just as well as the patients who
had everything disappear on the medical therapy and so there has
been a great increased interaction between the medical and surgical
parts of therapy. The other very important thing that allows us to
do is to learn more about how the treatments work and specifically
why they do not work, and so if there is a specific metastases that
has not gone away we can remove that both for the benefit of the
patient but also then to study that to try to find out what
characteristics are there that prevented that particular tumor from
responding to the treatment and by doing that we can find out why
those tumors are resistant and perhaps develop new therapies to
overcome those resistance mechanisms.

Foss
Mark, would you ever give some of these biological therapies before
you operated on a patient?

Faries
In the past, I would have definitely said if the tumor is
resectable we should resect it right away. We do not to want
to give it a chance to get to the point where we cannot take it
out. And in the past, the success for most of the
chemotherapies and other more standard older medical treatments for
melanoma, was so low that that would be a reasonable thing, but
with the improved efficacy of

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a number of these treatments, the chance of getting a response and
making it easier for us to do the surgery after the treatment is
pretty good and we learn more about the treatment by sequencing the
treatments in those orders. I think that will be something
that we do more and more as time goes on.

Foss
Harriet, we talk a lot about personalized medicine now and
identifying specific mutations in a patient's tumor and then
directing therapy towards specific genes that are mutated, and you
mentioned this new agent that is available targeting a specific
mutation in melanoma. Could you talk a little bit about
that?

Kluger
Yes, I think it the first incidence in cancer treatment where there
is a specific mutation that actually drives the cancer cell and is
not found in other cells in the body, so that enables us to give a
drug that targets that particular mutation and only that mutation,
and does not affect normal cells to the degree that other cancer
therapies do. This enabled the developers of this drug to
push the doses up in patients with very little side effects and
that is probably why this drug is so effective. For example,
in breast cancer you give targeted therapies as well, tamoxifen or
antihormonal therapy, and that is a targeted therapy against
estrogen receptor. But because estrogen receptor is located
in other parts of the body too, you are limited in how much of the
drug you can give in order to kill cancer cells. That is
probably why this drug has been so effective in melanoma and we are
hoping that going forward we are going to find additional mutations
that drive other subsets of melanomas, for example we know that
another 15% of the melanomas are driven by a mutation called N-ras
mutation, so if we had a drug that specifically targeted those
N-ras mutations we may be able to use that as well and we are
hoping that in the future we will have a menu of drugs that we can
give and from the menu we pick the best thing for the
patient. The flip side of that is trying to identify which of
the patients are going to respond to the immune therapies that we
mentioned because there the predictor would supposedly be found in
the immune system and not in the tumor, although we do not really
know that yet.

Foss
Where are we in terms of personalized medicine in melanoma? Are
these particular mutations screened for in all melanoma patients at
this point of time?

Kluger
We do at Yale as part of a research program. We have a grant
called the SPORE grant which stands for Special Programs of
Research Excellence, and it is a grant that has been given to us by
the National Cancer Institute and we are one of five melanoma
sites. The SPORE has some funding and what we call a tissue
core, so all of the specimens go to the core and that gives us the
opportunity to actually screen for these mutations. If it is
done in a routine pathology lab sometimes we have issues with
payment for the mutational analysis because it has not yet been FDA
approved and it is not recognized by all insurances.

Wilson
Do we think that the incidence of melanoma is increasing in
Connecticut because the disease is more common, or is it because we
are better at screening and detection, or both?

Kluger
We think it is the combination of both. Certainly nationally
the incidence is increasing but also the death rate for melanoma is
increasing, which leads one to believe that some degree of this
might be true increasing incidence rather than just an increasing
diagnosis, because people are more aware. Even though our
latitude is fairly far north, we still have a fairly large fair
population over here, we have the shoreline, and lakes and people
are outdoors quite a bit despite the weather.

Wilson
Do we have screening programs at Yale that are offered from time to
time?

Kluger
Yale Dermatology Associates does have a free screening day where
people can walk in and get a full body skin screen and there are
dermatologists within the dermatology department that focus on
screening for melanoma, that is their area of interest and their
area of research interest, so we have a bunch of really competent
dermatologists who do this on a regular basis.

Foss
Mark, for a patient who say had one of these very early superficial
melanomas removed, of which there are a growing number of patients
out there now, what kind of follow-up should that patient
expect?

Faries
There are really two things for the patient to watch out for as
time goes on. The first is the possibility that the first
melanoma might come back, might have spread somewhere else and
might reappear, and the risk of that depends a lot on the
characteristics of the original primary and then whether the nodes
were involved or not. Typically, that risk if fairly low and
the patient can be followed with physical examinations and just
regular routine testing. The other risk though that patients
need to worry about once they have had one melanoma is the risk of
getting a second melanoma and that risk is substantially higher
than the risk for someone who has never had melanoma, and over the
course of the rest of their life it might be between 5% and 10%, so
it is not a huge risk but it is substantial, particularly compared
to the patient that has never had melanoma. The most important
component of the follow-up for that is regular skin examinations
and that can be with the surgical oncologist, it can be with the
dermatologist, or their primary care physician and they can check
themselves as well, but if they undergo that sort of regular
surveillance program chances are if they do get a second melanoma,
it will be caught at least as early or usually earlier than the
first one and should not be a threat to the life and can be treated
and cured as well.

Wilson
Getting back to the biopsy or excision procedure in the sentinel
lymph procedure, is it something that the patient would have to
stay overnight in the hospital for, or do they go home that day and
what are some of the side effects that might be associated with say
a sentinel lymph node procedure?

Faries
The sentinel node procedure is a minimally invasive procedure, it
is outpatient surgery. It involves first a test which is a
radiology test where the site of the primary melanoma is injected
with a bit of radioactive trace, then can be followed to where this
sentinel lymph node is and then during the surgery, we also inject
a blue dye that allows us to see the sentinel node as well.
We find through

a small incision that node that has taken up those tracers, take
that node out, and close up the little incision. The patient
can then go home the same day, return to work generally within a
day or two and if that lymph node is okay, that means the rest of
the lymph nodes are almost certainly okay as well and they can
avoid any other more invasive, more substantial operations.

Foss
Harriet, you talked about the SPORE grant at Yale, which is a
research grant for melanoma. I wonder if you could talk to us
a little bit about clinical trials, ongoing clinical trials and new
developments in melanoma.

Kluger
We have a number of experimental therapies that we can offer
patients that are not available in routine oncology
practices. When we look at clinical trials and drug
development we go through a bunch of phases. Some of these
drugs are in the early phase of development, some are at later
stages of development, and we definitely have some really exciting
immune based therapies in the pipeline right now that hopefully
within a year or two will expand and we are seeing some very nice
responses to some of them, but on a regular basis we typically have
about six different experimental therapies available for patients
with metastatic melanoma.

Dr. Harriet Kluger is an Associate Professor of Medical
Oncology and a member of the Yale Cancer CenterMelanoma
Program. Dr. Mark Faries is an Associate Professor of
Surgical Oncology specializing in thetreatment of
melanoma.If you have questions for the doctors or would
like to share your comments, visityalecancecenter.org
where you can also subscribe to our pod cast and find written
transcripts of pastprograms. I am Bruce Barber and
you are listening to the WNPR Health Forum on the Connecticut
PublicBroadcasting Network.